Drugs for treating respiratory and nasal disorders are frequently administered in aerosol formulations through the mouth or nose. Peter Byron, Respiratory Drug Delivery, CRC Press, Boca Raton, FL 1990, provides a background for this form of therapy. (As used hereinafter the terms "aerosol drug formulation" and "inhalation drug formulation" are synonymous and refer to one or more physiologically active chemical compounds in combination with excipients such as surface-active agents, "surfactants" and propellants.)
One widely used method for dispensing such an aerosol drug formulation involves making a suspension formulation of the drug as a finely divided powder in a liquefied gas known as a propellant. The suspension is stored in a sealed container capable of withstanding the pressure required to maintain the propellant as a liquid. The suspension is dispensed by activation of a dose metering valve affixed to the container. A metering valve may be designed to consistently release a fixed, predetermined amount of the drug formulation upon each activation. As the suspension is forced from the container through the dose metering valve by the high vapor pressure of the propellant, the propellant rapidly vaporizes leaving a fast moving cloud of very fine particles of the drug formulation. This cloud is usually directed into the body of the patient by a channeling device, e.g., a cylinder like or cone like passage, with one of its ends attached to the outlet of the pressurized container, and the other end inserted in the mouth or nose of the patient. Concurrently with the activation of the aerosol dose metering valve, the patient inhales the drug formulation particles into the lungs or nasal cavity. Systems for dispensing drugs in this way are known as "metered dose inhalers (MDI's)." [Ibid Byron, Pages 167-207.]
Many materials, including drug formulations, have a tendency to aggregate (also referred to as "flocculate" or "clump-up") when stored as fine particles having dimensions of a few microns in a suspension. For an aerosol delivery system to work properly the particle size should generally not exceed about five microns. As the particle size exceeds five microns, it becomes increasing difficult to maintain an efficacious aerosol dose with a predicable dispersion pattern upon activation of the metering valve. Further, the suspension should be uniform, that is, substantially free from large aggregates of the drug particle and be substantially homogenous throughout the container.
To minimize or prevent the problem of aggregation of fine particles, compounds known as surface active agents, or surfactants, are used to coat the surfaces of the fine particles and assist in wetting the particles with an aerosol propellant. The use of surfactants in this way to maintain substantially uniform suspensions is said to "stabilize" the suspensions. An ideal surfactant should have a relative high affinity for the suspended drug formulation and be chemically and physically compatible with the propellant as well as the drug formulation. If it does not have these properties, the surfactant can possibly destabilize the suspension. Additionally, it must be essentially nontoxic.
For several years the chlorofluorocarbons (CFC's), for example, trichloromonofluoromethane, dichlorotetrafluoroethane and dichlorodifluoromethane, also known as "propellant 11" or "P 11", "propellant 114 or "P 114" and "propellant 12" or "P 12", respectively, have gained widespread acceptance as the propellants of choice for inhalation drug formulations. They are nonflammable, have low toxicity and reactivity, are compatible with many drug formulations and have the requisite physical attributes. See John Sciarra and Anthony Cutie, Theory and Practice of Industrial Pharmacy, Pages 589-619, Lea and Febiger, Philadelphia, 1986. However, in the past few years CFC's have been shown to cause depletion of the ozone layer of the atmosphere, a serious environmental problem. Scientists and governmental officials around the world have called for a phase-out of the use of CFC's. Some countries, e.g., Sweden, have completely banned the use of CFC's for aerosol products, while other counties have levied substantial taxes on them to encourage the use of other, environmentally safer propellants. See Dalby, et al., Pharmaceutical Technology, Mar. 26, 1990.
In recent years a nonchlorinated propellant chemically identified as 1,1,1,2-tetrafluoroethane also known as "propellant 134a" or "P 134a" has been promoted by major chemical manufacturers, notably DuPont and ICI, as an environmentally acceptable alternative to CFC propellants. Propellant 134a has physical properties comparable with P 12. Although like P 12 it is nonflammable and has a relatively low potential for interaction with a wide variety of products normally sold in aerosol form, its other chemical and solvent properties are different from P 12. For example P 134a is much less stable chemically than P 12 according to Dalby, et al. (see above).
Thiel in U.S. Pat. No. 4,357,789 teaches the use of propellan insoluble perfluorinated surface-active dispersing agents in CFC and perfluorinated propellants although P 134a is not specifically mentioned. These agents include perfluorinated sulfonamide alcohol phosphate esters and their salts, perfluorinated alkyl sulfonamide alkylene quaternary ammonium salts and perfluorinated alcohol phosphate esters and their salts. Thiel teaches that surfactants must insoluble in the propellant. Further, he teaches that the drug must be coated with the surfactant in an organic solvent dried, then added to the propellant mixture.